Kappa opioid receptor antagonists

ABSTRACT

Compounds of the formula:                    
     are provided, which are selective kappa opioid receptor antagonists, wherein R 1  is (C 1 -C 5 )alkyl, C 3 -C 6 (cycloalkyl)alkyl, C 5 -C 7 (cycloalkenyl)alkyl, (C 6 -C 12 )aryl, (C 6 -C 12 )aralkyl, trans(C 4 -C 5 )alkenyl, allyl or furan-2-ylalkyl, R 2  is H, OH or O 2 C(C 1 -C 5 )alkyl; R 3  is H, (C 6 -C 10 )aralkyl, (C 1 -C 5 )alkyl or (C 1 -C 5 )alkylCO; X is O, S or NY, wherein Y is H or (C 1 -C 5 ) alkyl; R 4  is CH 2  (methylene) or C═O (carbonyl), R 5  is CH 2 , C═O or C═NH (imino) and R 6  is (C 1 -C 4 )alkyl or NH(C 1 -C 4 )alkyl, optionally substituted by a non-terminal (C 1 -C 2 )alkyl group or by N(R 7 )(R 8 ) wherein R 7  and R 8  are individually H or (C 1 -C 3 )alkyl, with the proviso that one of R 4  or R 5  is CH 2 , and the pharmaceutically acceptable salts thereof.

This is a continuation of application Ser. No. 08/080,287, filed Jun.21, 1993, now U.S. Pat. No. 5,457,208.

This invention was made with the assistance of the Government under agrant from the National Institutes of Health (Grant No. DA 01533). TheU.S. Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Endogenous opioid peptides are involved in the mediation or modulationof a variety of mammalian physiological processes, many of which aremimicked by opiates or other non-endogenous opioid ligands. Some of theeffects that have been investigated are analgesia, tolerance anddependence, appetite, renal function, gastrointestinal motility, gastricsecretion, learning and memory, mental illness, epileptic seizures andother neurological disorders, cardiovascular responses, and respiratorydepression.

The fact that the effects of endogenous and exogenous opioids aremediated by at least three different types [mu (μ), delta (δ), kappa(κ)] of opioid receptors raises the possibility that highly selectiveexogenous opioid agonist or antagonist ligands might have therapeuticapplications. See W. R. Martin, Pharmacol. Rev., 35, 283 (1983). Thus,if a ligand acts at a single opioid receptor type or subtype, thepotential side effects mediated through other opioid receptor types canbe minimized or eliminated.

The prototypical opioid antagonists, naloxone and naltrexone, are usedprimarily as pharmacologic research tools and for the reversal of toxiceffects of opioids in case of overdose. Since these antagonists act atmultiple opioid receptors, their applications in other therapeutic areasor as pharmacologic tools appear to be limited. However, naltrexonerecently was reported to reduce the incidence of relapse in recoveringalcoholics by J. R. Volpicelli et al., Opioids, Bulimia and AlcoholAbuse and Alcoholism, L. D. Reid, ed., Springer-Verlag (1990) at pages195-214. Naloxone has been reported to suppress ethanol but not waterintake in a rat model of alcoholism. J. C. Froehlich et al., Pharm.Biochem. Behav., 35, 385 (1990).

Some progress has been made in the development of highly selectiveopioid antagonists. For example, Portoghese et al. (U.S. Pat. No.4,816,586) disclose certain opiate analogs which possess highselectivity and potency at delta receptors. Minimal involvement wasobserved at mu and kappa opioid receptors. One of the highly selectiveanalogs disclosed in U.S. Pat. No. 4,816,586 has been named“naltrindole” or “NTI,” and has the formula:

wherein X is NH. See P. S. Portoghese et al., J. Med. Chem., 31, 281(1988).

Portoghese et al. (U.S. Pat. No. 4,649,200) disclose substitutedpyrroles which exhibit selective antagonism at kappa opioid receptors.One such analog is norbinaltrophimine (norBNI), which has the formula:

The selectivities of these prototypical δ and κ opioid receptorantagonists have been attributed to the presence of nonpeptide “address”mimics which bear a functional relationship to key elements in theputative δ and κ addresses of enkephalin and dynorphin, respectively.See, P. S. Portoghese et al., Trends Pharmacol. Sci., 10, 230 (1989).Accordingly, the design of NTI employed a model that envisaged the Phe⁴phenyl group of enkephalin as a critical part of the δ address. See, P.S. Portoghese et al., J. Med. Chem., 33, 1714 (1990). Similarly, theaddress element conferring selectivity in norBNI has been suggested tobe a basic function that mimics the guanidinium moiety of Arg⁷ indymorphin, by P. S. Portoghese et al., J. Med. Chem., 31, 1344 (1988).

It has recently been reported that suppression of ethanol ingestion maybe mediated by the delta opioid receptor type. For example, the δantagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174864), stronglyinhibits ethanol drinking, but has a very short duration of action,which may limit its clinical utility. See J. C. Froehlich et al.,Psychopharmacol., 103, 467 (1991). Using NTI as an antagonist, M.Sofuoglu et al., J. Pharmacol. Exp. Ther., 257, 676 (1991) determinedthat the antinociceptive activity of two delta receptor agonistenkephalin analogs, DSLET and DPDPE, may be mediated by two discretedelta opioid receptor subtypes. It has also been suggested thatdevelopment of addiction and/or tolerance to opiates may be inhibited bydelta-opioid receptor antagonists, and that opioid-type delta-opioidreceptor antagonists may be useful as immunosuppressive agents.Likewise, compounds which are selective at mu receptors may be useful asanalgesics which do not exhibit the potentially harmful side effects ofless-selective analgesics such as morphine.

Therefore, a continuing need exists for compounds which are opioidreceptor-selective, i.e., which can act as agonists or antagonists withspecificity at the delta, mu or kappa opioid receptor, or at one of thesubtypes of these receptors.

SUMMARY OF THE INVENTION

The present invention is directed to biologically active compounds offormula (I):

wherein R¹ is (C₁-C₅)alkyl, C₃-C₆(cycloalkyl)alkyl,C₅-C₇-(cycloalkenyl)alkyl, (C₆-C₁₂)aryl, (C₆-C₁₂)aralkyl,trans-(C₄-C₅)alkenyl, allyl or furan-2-ylalkyl, R² is H, OH orO₂C(C₁-C₅)alkyl; R³ is H, (C₆-C₁₀)aralkyl, (C₁-C₅)alkyl or(C₁-C₅)alkylCO; X is O, S or NY, wherein Y is H or (C₁-C₅)-alkyl; R⁴ isCH₂ (methylene) or C═O (carbonyl), R⁵ is CH₂, C═O or C═NH (imino) and R⁶is (C₁-C₄)alkyl or NH(C₁-C₄)alkyl, optionally substituted by anon-terminal (C₁-C₂)alkyl group or by N(R⁷)(R⁸) wherein R⁷ and R⁸ areindividually H or (C₁-C₃)alkyl, with the proviso that one of R⁴ or R⁵ isCH₂, and the pharmaceutically acceptable salts thereof.

Using peptide antagonists of known binding selectivity as standards, itwas unexpectedly found that the compounds of the invention are selectiveantagonists at kappa opioid receptors, while exhibiting little or nobinding at delta or mu receptors. Thus, the present invention alsoprovides a method for blocking kappa opioid receptors in mammaliantissue comprising contacting said receptors in vivo or in vitro with aneffective amount of the compound of formula I, preferably in combinationwith a pharmaceutically acceptable vehicle. Thus, the compounds offormula I can be used as pharmacological and biochemical probes ofopiate receptor structure and function, e.g., to measure the selectivityof other known or suspected opioid receptor antagonists or agonists.Such tissue includes tissue of the central nervous system (CNS), thegut, the cardiovascular system, the lung, the kidney, reproductive tracttissue and the like. Therefore, the compounds of formula I which exhibitkappa receptor antagonist activity may also be therapeutically useful inconditions where selective blockage of kappa receptors is desired. Thisincludes blockage of the appetite response, blockage of paralysis due tospinal trauma and a variety of other physiological activities that maybe mediated through kappa receptors.

The alkyl moiety present in the R¹ group which links the cycloalkyl,cycloalkenyl, aryl, or furan-2-yl moiety to the basic nitrogen atom inthe compounds of formula I is a lower(alkyl) group, preferably—(CH₂)_(n)—, wherein n is about 1-5, most preferably n is 1, e.g., R¹ isC₃-C₆(cycloalkyl)methyl, C₅-C₇(cycloalkenyl)-methyl, arylmethyl orfuran-2-yl-methyl. Preferred aryl moieties include (C₆-C₁₀)aryl, i.e.,phenyl, benzyl, tolyl, napthyl, xylyl, anisyl and the like.

In structure I, a bond designated by a wedged or darkened line indicatesone extending above the plane of the R³O-substituted phenyl ring. A bonddesignated by a broken line indicates one extending below the plane ofthe phenyl ring.

Preferred compounds of the formula I are those wherein R¹ is(C₁-C₅)alkyl, C₃-C₆(cycloalkyl)alkyl or C₅-C₇-(cycloalkenyl)alkyl,preferably wherein R¹ is C₃-C₆(cycloalkyl)methyl, and most preferablywherein R¹ is cyclopropylmethyl. R² is preferably OH or OAc (O₂CCH₃),and R³ preferably is H. Preferably, X is NH or NCH₃, most preferably NH.Preferably, R⁶ is methyl, ethyl, propyl, butyl or 2-methylbutyl which isunsubstituted or is terminally substituted with N(CH₃)₂ or N(CH₂CH₃)₂.Preferably, R⁴ is CH₂ and R⁵ is C═O or C═NH.

Since the compounds of the invention are formally morphinan derivatives,it is believed that their ability to cross the “blood-brain barrier” andto affect the central nervous system (CNS) should be far superior topeptide opioid antagonists. For example, as disclosed in U.S. patentapplication Ser. No. 07/750,109, filed Aug. 26, 1991, both NTI and itsbenzofuran analog, NTB were found to produce unexpectedly prolongedsuppression of ethanol drinking in rats that were selectively bred forhigh voluntary ethanol drinking, as compared to peptidyl delta-opioidreceptor antagonists. Processes of preparing the compounds of formula Iare also aspects of the invention, as described hereinbelow, as are thenovel intermediates employed in the syntheses.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I wherein X is NH can be readily synthesized byreaction of a 4,5-epoxy-6-keto-morphinan such as naltrexone (6) with4-hydrazinobenzonitrile (D. E. Rivett et al., Austr. J. Chem., 32 1601(1979)) under Fischer indole conditions, as shown in Scheme I, to yieldthe 5′-nitrile 7.

Nitrile 7 was reduced to primary amine 8 using Raney Ni, and 8 wasreacted with the appropriate imidate esters, of the formulaCH₃OC(═NH)—R, to yield amidates of general formula II, wherein R isethyl, 2-methylbutyl, methyl, pentyl, propyl and butyl, respectively,for compounds 1-6.

See, S. R. Sandler et al., Organic Chemistry, Vol. 3, Academic Press, NY(1972) at pages 268-299; and E. Cereda et al., J. Med. Chem., 33, 2108(1990).

Compounds of formula I wherein R⁴ is C═O can be prepared by reacting amorphinan such as naltrexone with 4-carboxyphenylhydrazine to yield acompound of formula 7 wherein the 5′-CN group has been replaced by a5′-carboxy group, i.e., compound 15, hereinbelow. The 5′-carboxyintermediate is then amidated, e.g., with an alkylamine of the formulaH₂NR⁵R⁶, wherein R⁵ is CH₂ and R⁶ is as defined above, to yield thefinal products.

Compounds of formula I wherein R⁴ is CH₂ and R⁵ is C═O can be preparedby reacting the 5′-CH₂NH₂ group, i.e., of compound 8 with a carboxylicacid of the general formula HO₂CR⁶ wherein R⁶ is as defined above, inthe presence of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (“BOP Reagent,” Aldrich Chem. Co.).

Compounds of formula I wherein R⁴ is CH₂, R⁵ is C═NH and R⁶ isNH(C₁-C₄)alkyl, optionally substituted by non-terminal (C-C₂)alkyl or byN(R⁷)(R⁸) can be prepared by reacting, i.e., a compound of formula 8with a compound of the formula R⁶—C(OMe)═NH, wherein R⁶ is as definedimmediately above.

Compounds of formula I wherein X is O, S or NY can be prepared fromintermediates analogous to 7 or 8 wherein NH has been replaced by O, Sor NY. These intermediates can be prepared as generally disclosed inU.S. Pat. No. 4,816,586, which is incorporated by reference herein,which also discloses methods suitable for the preparation of salts ofcompounds of formula I.

The structures, common names and Merck Index reference numbers ofrepresentative 4,5-epoxy-6-ketomorphinan starting materials of generalformula (III) are summarized on Table I, below.

TABLE I (III)

Common Merck R¹ R² R³ Name No.² CH₂CH(CH₂)₂ OH H naltrexone 6209 CH₃ OHH oxymorphone 6837 CH₃ H H hydromorphone 4714 CH₃ H CH₃ hydrocodone 4687CH₂CH(CH₂)₂ H H — —¹ CH₂CH═CH₂ OH H naloxone 6208 CH₃ OH CH₃ oxycodone6827 ¹Preparation: M. Gates et al., J. Med. Chem., 7, 127 (1964). ²TheMerck Index, W. Windholz, ed., Merck & Co., Rahway, NJ (10th ed. 1983).

Other starting materials of the general formula III can be prepared bysynthetic methods which are well known in the art of organic chemistry.For example, compounds wherein R¹ is H and R³ is a suitable protectinggroup, and wherein the 6-keto group has also been protected, can beprepared from the compounds of formula III. These intermediates can beN-alkylated and deprotected to yield compounds of formula I wherein R¹is C₂-C₅(alkyl), C₄-C₆(cycloalkyl)alkyl, C₅-C₇(cycloalkenyl)alkyl, aryl,aralkyl, trans-C₄-C₅alkenyl or furan-2-ylalkyl, by the application ofwell-known reactions.

For example, the free hydroxyl groups of the compounds of formula III,e.g., R²=OH and/or R³=H, can be protected by acid-labile groups such astetrahydropyranlyl, trimethylsilyl, 1-methoxy-isopropyl and the like asdisclosed in Compendium of Organic Synthetic Methods, I. T. Harrison etal., eds., Wiley-Interscience, New York, N.Y. (1971) at pages 124-131,(hereinafter “Compendium”). The protection of the 6-keto group ofcompounds of Table I by its reversible conversion into a ketal or athioketal group is disclosed in Compendium, at pages 449-453. Methodsfor the demethylation of N-methyl amines have been disclosed, forexample, in Compendium at page 247, J. Amer. Chem. Soc., 89, 1942 (1967)and J. Amer. Chem. Soc., 77, 4079 (1955).

Procedures for the alkylation of secondary amines with halides underbasic or neutral conditions are well known. For example, see Compendiumat pages 242-245; Orq. Synth., 43, 45 (1963); J. Org. Chem., 27, 3639(1962) and J. Amer. Chem. Soc., 82, 6163 (1960).

Compounds of formula III wherein R² is acyloxy and/or R³ is acyl can beprepared by using the corresponding starting materials on Table I. Forexample, naltrexone can be diacylated by reacting it with theappropriate (C₁-C₅)alkyl anhydride for 10-18 hrs at 18-25° C. Theresultant 3,14-diacylated compound can be converted to the 14-acylatedcompound by limited hydrolysis. The 3-acylated starting materials can beprepared by the short-term reaction of the compounds of Table I with theanhydride, e.g., for about 2-4 hours. The 3-acylated product can beseparated from the 3,14-diacylated product by chromatography.

The acid salts of compounds of formula I wherein R³=H, can be convertedinto the corresponding (C₁-C₅)alkoxy derivatives [R³=(C₁-C₅)alkyl] bydissolving the starting material in DMF and adding an excess of theappropriate (C₁-C₅)alkyl iodide and an amine such asdiisopropylethylamine. The reaction can be conducted at an elevatedtemperature for about 4-10 hours. The final product can be purified bycolumn chromatography.

The invention also comprises the pharmaceutically acceptable salts ofthe biologically active compounds of formula I together with apharmaceutically acceptable carrier for administration in effective,non-toxic dose form. Pharmaceutically acceptable amine salts may besalts of organic acids, such as acetic, citric, lactic, malic, tartaric,p-toluene sulfonic acid, methane sulfonic acid, and the like as well assalts of pharmaceutically acceptable mineral acids such as phosphoric,hydrochloric or sulfuric acid, and the like. These physiologicallyacceptable salts are prepared by methods known in the art, e.g., bydissolving the free amine bases with an excess of the acid in aqueousalcohol.

In the clinical practice of the present method, the compounds of thepresent invention will normally be administered orally or parenterally,as by injection or infusion, in the form of a pharmaceutical unit dosageform comprising the active ingredient in combination with apharmaceutically acceptable carrier, which may be a solid, semi-solid orliquid diluent or an ingestible capsule or tablet. The compound or itssalt may also be used without carrier material. As examples ofpharmaceutical carriers may be mentioned tablets, intravenous solutions,suspensions, controlled-release devices, microcapsules, liposomes andthe like. Usually, the active substance will comprise between about 0.05and 99%, or between 0.1 and 95% by weight of the resultingpharmaceutical unit dosage form, for example, between about 0.5 and 20%of preparation intended for injection or infusion and between 0.1 and50% of preparation, such as tablets or capsules, intended for oraladministration.

The invention will be further described by reference to the followingdetailed examples, wherein melting points were taken using aThomas-Hoover Melting Point apparatus in open capillary tubes, and areuncorrected. NMR data was collected at ambient temperature on a BrukerAC-200 or a GE Omega 300, using DMSO-d₆, and TMS as the internalreference. IR data in each case was obtained from a KBr disk on aNicollet FT-IR instrument. Low resolution FAB mass data was obtained ona Finnigan 4000 instrument. Ion spray mass spectral data was obtainedfrom the Biochemistry Dept. Chemicals were supplied through Aldrich,except where noted. Naltrexone hydrochloride was obtained fromMallinkrodt, BOP reagent was obtained from Peptides International. TLCRf values were obtained on silica gel using the following solventsystems: (A) 33% EtOAc, 33% CHCl₃, 33% MeOH, 1% NH₃; (B) 95% CHCl₃, 5%MeOH, 0.1% NH₃; (C) 45% EtOAc, 45% MeOH, 5% NH₃. Analytical data wassupplied through M-H-W Laboratories, Phoenix, Ariz.

Physiological data for guinea pig ileal longitudinal muscle (GPI) wasobtained by the methodology of H. P. Rang, “Stimulant Actions ofVolatile Anaesthetics on Smooth Muscle,” Brit. J. Pharmacol., 22, 356(1964) on Dunkin-Hartley males; mouse vas deferens (MVD) data wasobtained using Henderson's method on Swiss-Webster males (G. Hendersonet al., “A New Example of a Morphine-Sensitive Neuroeffector Junction:Adrenergic Transmission in the Mouse vas Deferens,” Brit. J. Pharmacol.,46, 764 (1972). Guinea pig brain membrane binding assays were done onDunkin-Hartley males using a modification of the method of L. L. Werlinget al., “Opioid Binding to Rat and Guinea Pig Neural Membranes in thePresence of Physiological Cations at 37° C.,” J. Pharmacol. Exp. Ther.,233 722 (1985). In vivo assays were done s.c. on mice.

EXAMPLE 117-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-carboxy-6,7-2′,3′-indolomorphinanHydrochloride (15).

A mixture of naltrexone hydrochloride (2.0 g, 5.3 mmol) and4-carboxyphenylhydrazine (0.934 g, 6.14 mmol) in 80 mL glacial aceticacid was stirred at 85° C. under N₂ 24-72 hr. Solid product was removedfrom the cooled crude mixture by filtration, washed with glacial aceticacid, acetone, and then ether. The solid was dissolved in methanol anddried over sodium sulfate, filtered, and the solvent removed by rotaryevaporation, yielding 15 (1.8 g, 3.6 mmol, 68%). TLC(A) Rf 0.15. MS FAB(M+1) 459. IR COOH carbonyl, 1679 cm⁻¹.

EXAMPLE 217-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-cyano-6,7-2′,3′-indolomorphinanHydrochloride

Naltrexone hydrochloride (1.0 g, 2.65 mmol) and 4-hydrazinobenzonitrilehydrochloride (3.0 mmol) were mixed in a minimum amount of glacialacetic acid and 3 drops conc. HCl and stirred at 85° C. under nitrogenfor 72 hr. The cooled solution was poured into 150 mL ethyl acetate, andthe solid was filtered, washed with EtOAc, then ether, and air dried.Typical yields of 7 were 50-90%. TLC (A) Rf=0.74; (B) Rf=0.30. FTIR:nitrile at 2218 cm⁻¹. MS FAB (M+1) 440.

EXAMPLE 317-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-aminomethyl-6,7-2′,3′-indolomorphinan(8)

Nitrile 7 was reduced with H₂ (55 psi) in abs. methanol containing 10%NH₃ over Raney Ni for 4-7 days. After filtering, the solvent was removedon a rotary evaporator, and the product redissolved in EtOAc and washed4× with alkaline brine. The combined organic phases were dried on Na₂SO₄and MgSO₄, filtered, and the solvent was evaporated. Furtherpurification was done via silica gel centrifugal chromatography(Chromatatron) using solvent system (A), when needed. Product 8 was usedas the free base, with yields typically of 40-80%. TLC (A) Rf=0.25; (B)Rf=0.0; (C) Rf=0.62. MS FAB (M+1) 444. CHN: C₂₇H₃₁N₃O₃Cl₂. —H₂O.

EXAMPLE 417-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[(N²-acetamidino)methyl]-6,7-2′,3′-indolomorphinanDihydrochloride (3; II R=CH₃))

Amine 8 (as the free base, 127 mg, 0.286 mmol) and ethylacetimidatehydrochloride (39 mg, 0.315 mmol) were dissolved in abs. ethanol plus 3drops TEA and the mixture stirred 24 hr at 25° C. Solvents wereevaporated, and the product was dissolved in EtOAc, and precipitated asthe dihydrochloride salt, then recrystallized from hot EtOH/EtOAc toyield 133 mg of 3 (0.239 mmol, 83%); TLC (C) Rf=0.15. MS FAB (M+1) 485.CHN: C₂₉H₃₄N₄O₃Cl₂.NaCl.2H₂O ¹H NMR: 10.06 (bs, 1H, exch); 9.351 (bs,3H, exch); 9.05 (bs, 1H, exch); 8.911 (s, 1H, exch); 7.405 (s, 1H);7.387, 7.347 (d, 1H, J=8); 7.162, 7.124 (d, 1H, J=8); 6.718, 6.678 (d,1H, J=8); 6.600, 6.561 (d, 1H, J=8); 6.56 (s, 1H, exch); 5.705 (s, 1H,C₅β); 4.506 (bs, 2H); 4.209 (bs, 1H); 3.52, 3.408, 3.32 (m, 3H); 3.11(m, 2H); 3.03 (s, 2H); 2.68 (s, 1H); 2.66 (s, 1H) 2.137 (s, 3H); 1.768(d, 1H); 1.155 (m, 1H); 0.690 (m, 2H); 0.497 (m, 2H).

EXAMPLE 517-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[(N²-propanamidino)methyl]-6,7-2′,3′-indolomorphinanDihydrochloride (1; II, R=Et))

Amine 8 (300 mg, 0.677 mmol) and O-methyl propanimidate (molar excess)were dissolved in abs. EtOH and stirred at 50° C. until TLC showed nostarting material (24 hr). The crude reaction mixture was concentratedby rotary evaporation and added to brine at pH 10-11, and extracted withEtOAc. The organic phases were combined, dried over Na₂SO₄, and theproduct precipitated as the HCl salt, which was recrystallized fromethanol-ether, to yield 143 of 1, 0.29 mmol, 74%. TLC Rf (A) 0.34.MS(ion spray) (M+1) 499. CHN: C₃₀H₃₆N₄O₃Cl₂.2H₂O.NaCl. ¹H NMR: 11.335(s, 1H, exch); 10.056 (s, 1H, exch); 9.353 (s, 1H, exch); 9.166 (bs, 1H,exch); 8.910 (s, 1H, exch); 7.374 (s, 1H); 7.314, 7.285 (d, 1H, J=8.3);7.098, 7.070 (d, 1H, J=8.3); 6.593, 6.566 (d, 1H, J=8.1); 6.485, 6.456(d, 1H, J=8.1); 5.538 (s, 1H); 4.462, 4.453 (d, 2H, J=2.6); 3.605 (m,1H); 3.345 (s, 1H); 3.206 (s, 1H); 3.141 (s, 1H); 2.951, 2.934 (d, 1H,J=5.1); 2.84 (m, 1H); 2.804 (bs, 2H); 2.751 (s, 1H) 2.626 (m, 1H);2.446, 2,422, 2.398, 2.374 (m, 2H, J=7.2); 2.353, 2.329 (m, 1H); 1.870(s, 1H); 1.638, 1.602 (d, 1H, J=10.8); 1.143, 1.118, 1.093 (t, 3H,J=7.5); 0.957 (m, 1H); 0.550 (m, 2H); 0.253 (m, 2H).

EXAMPLE 617-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[(N²-3-methylpentanamidino)methyl]-6,7-2′,3′-indolomorphinanDihydrochloride (2, II, R=2-Methyl-butyl)

Amine 8 dihydrochloride (200 mg, 0.39 mmol) and a molar excess ofO-methyl 3-methylpentanimidate were dissolved in abs. EtOH with TEA andstirred at 50° C. until TLC showed no starting material (24 hr). Theresidue from the crude reaction mixture was filtered and washed withsmall portions of cold ethanol, dissolved in MeOH, dried over Na₂—SO₄.Product was precipitated as the HCl salt, and recrystallized fromethanol-ether to yield 69 mg of 2 (0.112 mmol, 29%); TLC (A) Rf 0.48.MS(ion spray) (M+1) 541. CHN: C₃₃H₄₂N₄O₃Cl₂.1.5H₂O.2NaCl. ¹H NMR: 11.384(s, 1H, exch); 9.954 (s, 1H, exch); 9.243 (bs, 2H, exch); 9.012 (s, 1H,exch); 8.861 (s, 1H, exch); 7.334 (s, 1H); 7.305, 7.281 (d, 1H, J=7.2);7.098, 7.074 (d, 1H, J=7.2); 6.619, 6.594 (d, 1H, J=7.5); 6.534, 6.509(d, 1H, J=7.5); 6.477 (s, 1H, exch); 5.632 (s, 1H, 5Cβ); 4.474, 4.458(d, 2H, J=4.8); 4.141, 4.112 (d, 1H, J=8.7); 3.25 (m, 2H); 2.922 (m,2H); 2.780, 2.768 (d, 1H, J=3.6); 2.605 (dd or q, 1H); 2.20-2.138 (m,2H); 1.825, 1.805-1.744 (m, 2H) 1.322-1.196 (m, 1H); 1.147, 1.122,1.106, 1.082 (dd, 2H, J=7.3); 0.834 (m, 1H); 0.822, 0.793, 0.764 (t, 3H,J=8.7); 0.785, 0.765 (d, 3H, J=6.0); 0.586 (m, 2H); 0.387 (m, 2H).

EXAMPLE 717-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[(N²-butyramidino)methy]-6,7-2′,3′-indolomorphinanDihydrochloride (5, II, R=Pr).

Amine 8 (200 mg, 0.45 mmol) and a molar excess of O-methyl butyrimidatewere heated in 20 mL abs. ethanol at 50° C. for 24 hr with stirring. Thesolvent was concentrated, and the reaction mixture was poured into ethylacetate to precipitate the product. The product was filtered and washedwith ether, then redissolved in ethanol and dried on sodium sulfate. Theproduct was then converted to the hydrochloride salt, and precipitatedfrom ether. The precipitate was recrystallized from ethanol-ether anddried under high vacuum to yield product 5 (156 mg, 0.27 mmol, 66%). TLC(A) Rf 0.18 (free base), 0.50 (salt). MS(ion spray) (M+1) 513. CHN:C₃₁H₃₈N₄O₃Cl₂.H₂O.NaCl. ¹H NMR: 11.400 (s, 1H, exch); 9.929 (bs, 1H,exch); 9.293 (s, 2H, exch); 9.242 (bs, 1H, exch); 8.987 (bs, 1H, exch);8.851 (bs, 1H, exch); 7.393, 7.350 (d, 1H, J=8); 7.377 (s, 1H); 7.141,7.098 (d, 1H, J=8); 6.679, 6.639 (d, 1H, J=8); 6.600, 6.559 (d, 1H,J=8); 6.482 (s, 1H, exch); 5.697 (s, 1H, C₅p); 4.480 (d, 2H); 4.148 (d,1H); 3.25 (d, 1H); 3.109 (s, 1H); 2.987 (t, 2H); 3.0-2.82 (m, 2H); 2.675(m, 2H) 2.433 (m, 2H); 2.396-2.307 (m, 1H); 1.828, 1.777 (d, 1H, J=10);1.680, 1.644, 1.606, 1.569 (quint, 2H, J=7); 1.099 (m, 1H); 0.896,0.859, 0.822 (t, 3H, J=7); 0.680 (m, 2H); 0.484 (m, 2H).

EXAMPLE 817-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5-[(N²-pentanamidino)methyl]-6,7-2′,3′-indolomorphinanDihydrochloride (6, II. R=Bu)

Amine 8 (200 mg, 0.45 mmol) and a molar excess of O-methylvalerimidatewere heated in 20 mL abs. ethanol at 50° C. for 24 hr with stirring. Thesolvent was concentrated, and the reaction mixture was poured into ethylacetate to precipitate the product, which was filtered and washed withether.

The residue was redissolved in ethanol, dried on sodium sulfate andconverted to the hydrochloride salt. The salt was precipitated fromether, recrystallized from ethanol-ether and dried under high vacuum toyield δ (88 mg, 0.15 mmol, 33%). TLC (A) Rf 0.11 (free base), 0.50(salt). MS(ion spray) (M+1) 527. CHN: C₃₂H₄₀N₄O₃Cl₂.1.5H₂O.NaCl. ¹H NMR:11.440 (s, 1H, exch); 10.026 (bs, 1H, exch); 9.315 (bs, 2H, exch); 9.1(bs, 1H, exch); 8.897 (s, 1H, exch); 7.394 (s, 1H); 7.377, 7.349 (d, 1H,J=8); 7.138, 7.109 (d, 1H, J=8); 6.675, 6.646 (d, 1H, J=8); 6.585, 6.557(d, 1H, J=8); 5.683 (s, 1H, C5β); 4.505 (bs, 2H); 4.168 (bs, 1H); 3.669(s, 1H); 3.30 (m, 1H); 3.084 (m, 1H); 3.010, 2.966 (m, 2H); 2.649 (m,1H); 2.53 (m, 1H); 2.458, 2.434, 2.405 (t, 2H); 2.081 (s, 1H) 1.796,1.759 (d, 1H, J=11); 1.61-1.55 (quint, 2H); 1.30-1.22 (m, 2H); 1.12 (m,1H); 0.883, 0.857, 0.833 (t, 3H, J=7.5); 0.70 (m, 1H); 0.63 (m, 1H);0.48 (m, 1H); 0.43 (m, 1H).

EXAMPLE 917-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[N-(β-diethylamino)ethylcarboxyamido]-6,7-2′,3′-indolomorphinanDihydrochloride (38)

Compound 15 (200 mg, 0.377 mmol) in 25 mL dry dichloromethane wasbrought into solution dropwise with triethylamine. BOP reagent (170 mg,0.385 mmol) and N,N-diethylethylenediamine (90 mg, 0.75 mmol, 0.1 mL)were added, and the solution was stirred at 25° C. for 24 hr. Thereaction mixture was added to ethyl acetate (150 mL), washed 3× withbrine at pH 10, and the organic phase dried on sodium sulfate andmagnesium sulfate, filtered, and concentrated. The residue was convertedto the HCl salt using methanolic HCl and precipitated from ethylacetate. The product was recrystallized from ethanol-ether, and driedunder high vacuum, to yield 217 mg of 38 (0.345 mmol, 91%). TLC (A) Rf0.49; MS(ion spray) (M+1) 557. CHN: C₃₃H₄₂N₄O₄Cl₂.3.5H₂O. ¹H NMR: 10.6(s, 1H, exch); 9.343 (bs, 1H, exch); 9.032 (bs, 1H, exch); 8.889 (t, 1H,exch); 8.62 (bs, 1H, exch); 8.106 (s, 1H); 7.778, 7.734 (d, 1H, J=8);7.413, 7.370 (d, 1H, J=8); 6.699, 6.658 (d, 1H, J=8); 6.613, 6.572 (d,1H, J=8); 6.57 (s, 1H, exch); 5.705 (s, 1H, C5β); 4.152 (d, 1H); 3.644(m, 2H); 3.527, 3.484 (d, 1H, J=8); 3.190-3.133 (m, 8H as 4(—NCH₂—)];3.024 (s, 1H); 2.679 (m, 2H); 2.586 (s, 1H); 2.43 (d, 2H) 1.831, 1.784(d, 1H, J=9); 1.262, 1.227, 1.191 (t, 6H); 1.16 (m, 1H); 0.683 (m, 2H);0.485 (m, 2H).

EXAMPLE 1017-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[N²-(N,N-dimethylglycinamidino)methyl]-6,7-2′,3′-indolomorphinanTrihydrochloride (42, II, R=CH₂NMe₂)

Amine 8 (160 mg, 0.36 mmol) and O-methyl (N,N-dimethyl)-glycinimidate(free base, molar excess), were dissolved in abs. ethanol and maintainedwith stirring at 50° C. for 72 hr. The solution was concentrated, thenpoured into ethyl acetate to precipitate the product. The product wasrecrystallized from ethanol-ether, and converted to the hydrochloridesalt to yield 42 (83 mg, 0.13 mmol, 36%). TLC (A) Rf=0.10, (C) Rf=0.30.MS (FAB) 528 (M+1). CHN: C₃₁H₄₀N₅O₃Cl₃.0.3NaCl.C.₂H₆O. ¹H NMR: 11.404(s, 1H, exch); 10.35 (br, 1H, exch); 9.556 (br, 2H, exch); 9.268 (s, 1H,exch); 8.963 (br, 1H, exch); 7.423 (s, 1H); 7.338, 7.309 (d, 1H, J=8.7);7.163, 7.135 (d, 1H, J=8.4); 6.643, 6.619 (d, 1H, J=7.2); 6.554, 6.525(d, 1H, J=8.7); 6.505 (s, 1H, exch); 5.652 (s, 1H, C₅H); 4.567 (s, 2H);4.161, 4.141 (d, 1H, J=6); 3.471 (m, 1H); 3.402 (s, 1H); 3.353 (m, 1H);3.297, 3.272 (d, 1H, J=6.3); 3.122, 3.102 (d, 1H, J=6); 3.037 (s, 1H);2.984 (s, 1H); 2.667 (m, 2H); 2.582 (m, 1H); 2.533 (s, 1H); 2.504 (s,6H, N(CH₃)₂); 1.812, 1.775 (d, 1H, J=11); 1.142 (m, 1H); 0.715 (m, 1H)0.634 (m, 1H); 0.524 (m, 1H); 0.439 (m, 1H).

EXAMPLE 1117-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-51′-[(4-dimethylaminobutyryl)aminomethyl]-6,7-2′,3′-indolomorphinanDihydrochloride (43)

Compound 8 (as the free base, 179 mg, 0.404 mmol) was combined with4-dimethylaminobutyric acid (75 mg, 0.444 mmol) and BOP reagent (200 mg,0.452 mmol) in dry CH₂Cl₂ and stirred at 25° C. 24 hr. The crude mixturewas poured into 150 mL ethyl acetate and washed 3× with alkaline brine.The organic portion was dried on Na₂SO₄, and precipitated as the HClsalt with methanolic HCl, to yield 82 mg of 43 (0.130 mmol, 32%). TLC(A) Rf=0.34. MS (FAB) 557 (M+1). CHN: C₃₃H₄₂N₄O₄Cl₂.2H₂O.0.5NaCl. ¹HNMR: 11.250 (s, 1H, exch); 10.75 (br, 1H, exch); 9.231 (s, 1H, exch);8.943 (br, 1H, exch); 8.427, 8.410, 8.390 (t, 1H, J=5.1 and 6); 7.269,7.240 (d, 1H, J=8.7); 7.167 (s, 1H); 7.001, 6.972 (d, 1H, J=8.7); 6.631,6.603 (d, 1H, J=8.4); 6.550, 6.521 (d, 1H, J=8.7); 6.395 (s, 1H, exch);5.636 (s, 1H, C₅H); 4.255, 4.238 (d, 2H, J=5.1); 4.141, 4.125 (d, 1H,J=4.8); 3.418, 3.410 (d, 1H, J=5.1); 3.353 (s, 1H); 3.247 (s, 1H); 3.202(m, 1H); 3.105 (s, 1H); 3.048 (s, 1H); 2.971 (s, 1H); 2.942, 2.930 (d,1H, J=8.7); 2.650 (s, 6H); 2.585 (s, 1H); 2.195, 2.171, 2.146 (t, 2H,J=7.2 and 7.5); 1.854 (m, 2H); 1.768, 1.732 (d, 1H, J=11); 1.085 (m,1H); 0.680 (m, 1H); 0.607 (m, 1H); 0.448 (m, 1H); 0.416 (m, 1H).

EXAMPLE 1217-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[N²-(4-dimethylaminobutyrylamidino)methyl]-6,7-2′,3′-indolomorphinanTrihydrochloride (44, II, R=CH₂CH₂CH₂—NMe₂)

Amine 8 (free base, 220 mg, 0.497 mmol) and O-methyl4-(dimethylamino)butyrimidate (free base, molar excess) were dissolvedin abs. ethanol and maintained with stirring at 50° C. for 72 hr. Thesolution was concentrated, then added to ethyl acetate to precipitatethe product. The product was recrystallized from ethanol-ether andconverted to the hydrochloride salt, to yield product 44 (95 mg, 0.143mmol, 29%). TLC (A) Rf=0.0, (C) Rf=0.09. MS (FAB) 556 (M+1). CHN:C₃₁H₄₄N₅O₃Cl₃.1.5H₂O.0.5NaCl0.5C₂H₅OH. ¹H NMR: (taken as the free base)11.252 (s, 1H); 7.303 (s, 1H); 7.295, 7.268 (d, 1H, J=8.1); 7.056, 7.029(d, 1H, J=8.1); 6.561, 6.534 (d, 1H, J=8.1); 6.461, 6.434 (d, 1H,J=8.1); 5.480 (s, 1H, C₅H); 4.745 (s, 1H); 4.345 (s, 2H); 3.269, 3.250(d, 2H, J=5.7); 3.089 (s, 1H); 3.025 (s, 1H); 2.728 (m, 1H); 2.694 (m,1H); 2.681 (s, 1H); 2.489, 2.467 (d, 2H, J=6.6); 2.408, 2.386 (d, 2H,J=6.6); 2.293 (m, 3H); 2.157 (m, 3H); 2.052 (s, 6H); 1.601, 1.564 (d,1H, J=11); 0.883 (m, 2H); 0.488 (m, 2H); 0.159, 0.144 (d, 2H, J=4.5).

EXAMPLE 1317-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-5′-[N-(β-dimethylamino)ethylcarboxamido]-6,7-2′,3′-indolomorphinanDihydrochloride (45)

Compound 15 (200 mg, 0.377 mmol) in 25 mL dry dichloromethane wasbrought into solution by dropwise addition of triethylamine. BOP reagent(170 mg, 0.385 mmol) and N,N-dimethylethylenediamine (66 mg, 0.75 mmol,0.08 mL) were added, and the solution was stirred at 25° C. for 5 hr.The reaction mixture was added to ethyl acetate (150 mL) and washed 3×with brine at pH 10. The organic phase was dried over sodium sulfate andmagnesium sulfate, filtered, and concentrated. The free base wasprecipitated from hexane to remove TEA and N,N-dimethylethylenediamine,then converted to the HCl salt and precipitated from ethyl acetate. Theprecipitate was recrystallized from ethanol-ether and dried at highvacuum to yield 123 mg of 45, 0.204 mmol, 54%. TLC (A) Rf=0.28; MS(ionspray) (M+1) 529. CHN: C₃₁H₃₈N₄O₄Cl₂.H₂O. ¹H NMR: 11.678 (s, 1H, exch);10.657 (s, 1H, exch); 9.343 (bs, 1H, exch); 9.030 (bs, 1H, exch); 8.803,8.787, 8.769 (t, 1H, exch, amide NH); 8.095 (s, 1H); 7.773, 7.746 (d,1H, J=8); 7.413, 7.370 (d, 1H, J=8); 6.685, 6.657 (d, 1H, J=8); 6.603,6.577 (d, 1H, J=8); buried, 6.58 (s, 1H, exch, C₁₄—OH); 5.700 (s, 1H,C₅β); 4.163 (bs, 1H); 3.669, 3.649, 3.632, 3.612 (qt, 2H); 3.259, 3.240,3.220 (t, 2H); 3.28 (m, 1H); 3.089 (m, 2H); 3.034 (s, 1H); 2.988 (m,1H); 2.88-2.86 (m, 1H); 2.658 (m, 1H); 2.572 (s, 1H); 1.817, 1.784 (d,1H, J=10); 1.141 (m, 1H); 0.692 (m, 1H); 0.647 (m, 1H); 0.487 (m, 1H);0.452 (m, 1H).

EXAMPLE 14 Evaluation of Antagonist and Agonist Activity

A. Smooth Muscle Assays

1. Guinea Pig Ileal Longitudinal Muscle (GPI). Ilea from guinea pigswere taken approximately 10 cm from the ileocecal junction, and a stripof longitudinal muscle with the myenteric plexus attached was preparedby the method of H. B. Rang et al., Brit. J. Pharmacol., 22, 356 (1964).A 1 cm portion of this strip was then mounted between two platinumelectrodes placed in a 10 ml organ bath and connected to an isometrictransducer; contractions were recorded on a polygraph. Contractions ofthe ileal strip were initiated by supramaximal rectangular pulses in allpreparations (80 V of 0.5 ms duration at a frequency of 0.1 Hz). Krebsbicarbonate solution containing 1.25 μM chlorpheniramine maleate was thebathing solution and was continuously bubbled with 95% O₂ and 5% CO₂.The organ bath was maintained at 36°-37° C. The longitudinal musclestrip was allowed to equilibrate with continuous stimulation for aminimum of 90 min. Cumulative concentration-response curves weredetermined after drugs were added to the bath in preselected amounts andwashed out with buffer after noting their maximum effects.

2. Mouse Vas Deferens (MVD). This assay was performed according to thedescription by G. Henderson et al., Brit. J. Pharmacol., 46, 764 (1972).Both vasa deferentia were dissected out of mice and mounted singlythrough two platinum ring electrodes in a 10 ml organ bath. The bathcontained Krebs bicarbonate solution that was continuously bubbled with95% O₂ and 5% CO₂. The organ bath was maintained at 37° C. The tissuewas attached to an isometric transducer and stimulated transmurally withrectangular pulses (0.1 Mz, 1 ms duration, supramaximal voltage). Drugswere added cumulatively to the bath in preselected amounts and washedout after noting their maximum effects.

B. Pharmacology

Each compound (100 nM) was incubated for 15 min with the mouse vasdeferens (MVD) and guinea pig ileum (GPI) preparations prior to addinggraded doses of a standard agonist for determination of an IC₅₀ value.The standard agonists employed were [D-Ala², D-Leu⁵]enkephalin (DADLE)(D), morphine (M), and ethylketazocine (EK); these are selective fordelta (D), mu (M) and kappa (EK) opioid receptors.Concentration-response curves were obtained in the absence (control) andthe presence of the antagonist are expressed as IC₅₀ values. The IC₅₀ratio represents the IC₅₀ in the presence of the antagonist divided bythe control IC₅₀ value in the same tissue. Therefore, a high IC₅₀ ratiorepresents a correspondingly high degree of antagonism at a particularreceptor. This IC₅₀ ratio was employed to calculate the Ke value usingthe equation Ke=[antagonist]/(IC₅₀ ratio-1). Therefore, a low Kerepresents a correspondingly high degree of binding at a particularreceptor. The results of these bioassays are summarized on Table II,below.

TABLE II

EK^(a) (GPI) M^(a) (GPI) D^(a D)(MVD) Selectivity Compound number &structure (R=)^(b) Ke^(e) IC₅₀ ^(c) ratio^(d) Ke IC₅₀ ratio Ke IC₅₀ratio κ/μ κ/δ alkyd-amidines:

0.81 nM 124 ± 33 8.04 nM 13.4 ± 2.2 f 2.81 ± 0.62 9 44

0.66 nM 159 ± 43 9.71 nM 11.3 ± 2.6 f 2.28 ± 0.57 14 69

0.54 nM 185 ± 49 5.84 nM 18.2 ± 3.9 f 3.00 ± 0.51 10 62

0.23 nM 439 ± 100 6.80 nM 15.7 ± 4.0 26.9 nM 4.71 ± 1.06 28 93

0.25 nM 394 ± 97 3.27 nM 31.6 ± 10.7 f 1.19 ± 0.51 12 310 Amide-amines:

0.568 nM 177 ± 54 3.41 nM 30.3 ± 3.6 f 1.51 ± 0.42 6 117

(10 nm) 0.320 nM 31.8 ± 7.7 (50 nm) 3.14 nM 17.1 ± 2.1 (100 nM) f 1.95 ±0.56 16 329

0.505 nM 199 ± 62 5.56 nM 19.0 ± 6.2 f 1.20 ± 0.72 10 166amidine-amines:

0.183 nM 547 ± 125 11.1 nM 10.0 ± 0.4 25.6 nM 4.91 ± 1.38 55 111

0.147 nM 679 ± 273 9.01 nM 12.1 ± 3.4 f 2.71 ± 0.44 61 250norBinaltorphimine 0.56 nM (179) 14 nM (8.14) 14 nM (8.14) 22 22^(a)Agonists: kappa (EK) (ethylketazocine) mu (M) (morphine) delta (D)(DADLE) ^(b)All antagonist concentrations were 100 nM except wherenoted. ^(c)IC₅₀ = conc. of drug producing 50% inhibition of maximumresponse. ^(d)IC₅₀ ratio = IC₅₀ agonist + antagonist/IC₅₀ agonist ^(e)Ke= [antagonist]/IC₅₀ ratio-1. ^(f)The Ke value cannot be determinedbecause the IC₅₀ ratio is not significantly different from 1.

The compounds tested showed little or no agonistic activity in eitherthe GPI or MVD preparation. However, the compounds showed significantantagonistic potency toward the kappa opioid receptor agonist,ethylketazocine (EK), in the GPI. This was manifested by displacement ofthe EK concentration-response curve to higher concentration by factorsup to 680 (IC₅₀ ratio) in the presence of 100 nM of the test compounds.These results contrast with the observation that these compounds areconsiderably less effective in antagonizing the effect of morphine (a mureceptor-selective agonist). In this connection, it can be seen that themorphine IC₅₀ ratios at the same concentration of antagonist (100 nM)are not greater than one-sixth of those IC₅₀ ratios obtained with EK.Likewise, the EK results contrast with the observation that thesecompounds have considerably less ability to antagonize the activity ofDADLE (delta-receptor agonist) at the same antagonist concentration (100nM). This is demonstrated by IC₅₀ ratios not greater than one-thirtiethof those ratios obtained with EK. Thus, the compounds are highlyselective kappa-opioid receptor antagonists. Compounds 2, 5, 6, 38, 42,43, and 44 are all more potent than the most potent known kappaantagonist, norBNI (norBinaltorphimine), and of these, 6, 42, and 44,are also more selective. Of these ompounds, it appears that 44 possessesthe greatest poteny and selectivity.

Compound δ was tested in vivo using the mouse writhing procedure of G.Hayashi et al., Eur. J. Pharmacol., 85, 163 (1982). It is believed thatthis response is mediated by kappa receptors. Mice were treated with 50nmol of the agonist (morphine, DADLE, or the kappa selective agonistU50488H) and the 6 was administered subcutaneously (sc) at 4 mg/kg. TheED₅₀ ratios [(agonist +6)/−agonist control] for morphine, DADLE, andU50488H, respectively were 1.63, 0.25, and 3.77. Therefore, the observedinhibition exhibited by 6 of the writhing inhibition of morphine, DADLE,or U50488H in the whole animal model correlates with that observed invitro, and demonstrates that 6 is indeed a selective kappa antagonist.

C. Discussion

The 5′-substituted naltrindole compounds listed on Table II display aunique pharmacological profile in that they exhibit substantiallygreater antagonist potency at kappa-opioid receptors than at mu or deltaopioid receptors. Moreover, compounds 6, 42, and 44 are more potent andselective than the selective kappa antagonist, norBNI. The in vivoantagonist selectivity parallels that observed in the GPI preparation.Because these compounds exhibit no agonist effect in GPI or MVD, thesecan be regarded as “Pure” kappa opioid receptor antagonists. Therefore,compounds 6, 42, 44, and the other compounds of the present inventionwhich exhibit kappa opioid receptor antagonist activity should be usefulfor pharmacological studies of opioid receptor activity and function andmay be therapeutically useful in conditions where selective blockage ofkappa receptors is desired. This includes blockage of the appetiteresponse, blockage of paralysis due to spin al trauma, and a variety ofother physiologic activities that may be mediated through kappareceptors.

All publications, patents and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula:

wherein R¹ is (C₁-C₅)alkyl, C₃-C₆(cycloalkyl)alkyl,C₅-C₇(cycloalkenyl)alkyl, (C₆-C₁₂)aryl (C₇-C₁₂)aralkyl,trans(C₄-C₅)alkenyl, allyl or furan-2-ylalkyl, R² is H, OH orO₂C(C₁-C₅)alkyl; R³ is H, (C₇-C₁₀)aralyl, (C₁-C₅)-alkyl or(C₁-C₅)alkylCO; X is O, S or NY, wherein Y is H or (C₁-C₅)alkyl; R⁴ isCH₂ or C═O, R⁵ is CH₂, C═O or C═NH and R⁶ is (C₁-C₄)alkyl orNH(C₁-C₄)alkyl, optionally substituted by a non-terminal (C₁-C₂)alkylgroup or by N(R⁷)(R⁸) wherein R⁷ and R⁸ are individually H or(C₁-C₃)alkyl, with the proviso that one of R⁴ or R⁵ is CH₂, and thepharmaceutically acceptable salts thereof.
 2. A compound of claim 1wherein R¹ is C₃-C₆(cycloalkyl)C₁-C₅(alkyl).
 3. A compound of claim 2wherein R¹ is C₃-C₆(cycloalkyl)-methyl.
 4. A compound of claim 3 whereinR¹ is cyclopropyl-methyl.
 5. A compound of claim 1 wherein R² is H, OHor OAc.
 6. A compound of claim 5 wherein R³ is H.
 7. A compound of claim1 wherein X is O, NH or NCH₃.
 8. A compound of claim 1 wherein R⁴ is CH₂and R⁵ is C═NH.
 9. A compound of claim 1 wherein R⁶ is (C₁-C₄)alkyl,optionally substituted by a nonterminal CH₃ group, N(CH₃)₂ orN(CH₂CH₃)₂.
 10. A method for selectively blocking the binding of a kappaopioid-receptor agonist to kappa opioid receptors in mammalian tissuecomprising said receptors, said method comprising contacting said tissuewith an effective amount of a compound of claim 1 to block saidreceptors.